Progesterone Receptor Modulators for Use in the Therapy of Uterine Fibroids

ABSTRACT

The present invention relates to a long-term therapy including repeated treatment courses of ulipristal acetate or any metabolite thereof for treating uterine fibroids. The present invention also relates to a combined therapy applying ulipristal acetate with a progestin in order to improve the currently used treatment for uterine fibroids.

TECHNICAL FIELD

The present invention relates to efficient long-term therapy includingperiodically repeated treatment courses for treating uterine fibroids.The present invention also relates to a combined therapy in order toimprove the currently used treatment for uterine fibroids.

BACKGROUND OF THE INVENTION

Patients suffering from uterine fibroids require intervention in orderto improve the diseases' symptoms.

Uterine fibroids, which also called leiomyomata are common pelvicfibroid tumors occurring in up to 20% of women over 30 years of age.Leiomyomata represent one of the most frequent indications of surgicalprocedures in woman of reproductive age. Studies show that up to 77% ofwomen have microscopic or macroscopic uterine fibroids at the time ofmenopause (Cramer et al, 1990). Leiomyomata may be 1 mm to 20 cm indiameter. Usually, treatment choice is guided by the patient's age anddesire to preserve fertility and/or her uterus.

Most fibroids are asymptomatic but nearly half of women with fibroidshave significant and often disabling symptoms including menorrhagia,pelvic pain, dysmenorrhea and pressure effects. In addition, fibroidsthat distort the uterine cavity can have adverse effects on fertility(American Society for Reproductive Medicine. Myomas and reproductivefunction. Fertil Steril 2008; 90:S125-S130 and Somigliana E, VercelliniP, Daguati R, et al. Fibroids and female reproduction: a criticalanalysis of the evidence. Hum Reprod Update 2007; 13:465-76 andKolankaya A, Arici A. Myomas and assisted reproductive technologies:when and how to act? Obstet Gynecol Clin North Am 2006; 33:145-52 andDonnez J, Jadoul P. What are the implications of myomas on fertility? Aneed for a debate? Hum Reprod 2002; 17:1424-30.).

In such women, heavy uterine bleeding is a leading reason for medicalconsultation, surgery and work days lost (Collins J, Crosignani P G.Endometrial bleeding. Hum Reprod Update 2007; 13:421-31).

Over the last few years a variety of non-invasive treatments has becomeavailable to women with symptomatic fibroids and provides alternativesto the surgery.

Among others the use of anti-progestational agents before a surgicaltreatment has also been proposed to shrink uterine leiomoymata(WO2007/103510) or to render the patient amenorrheic. More specifically,WO2007/103510 relates to the treatment of uterine fibrosis usingeffective low doses of anti-progestational agent and length of treatmentis shorter than previously thought possible.

A number selective progesterone receptor modulators (SPRMs) are underdevelopment for the treatment of gynecological diseases such as uterinefibroid, endometriosis, adenomyosis, abnormal uterine bleeding anddysfunctional uterine bleeding.

SPRMs such as ulipristal acetate (UPA) offer a unique potential clinicalapplication in gynecology because effectively controls excessivebleeding, abdominal pain and size of myoma due to uterine fibroids andconsequently improve the quality of life of the patients.

WO2008/083192 relates to formulations for improving the bioavailabilityof ulipristal acetate as one of the antiprogestins can be advantageouslyused inter alia to antagonize endogenous progesterone. Ulipristalacetate is cited as a possible antiprogestin amoung a large number ofother relevant compounds. This patent application also provides a longlist of disorders which might be treated by the claimed composition.Uterine fibroids is cited as one possible disease to cure among others.In the application use of UPA for the treatment of uterine fibroids isnot explored explicitly and no examples are described in order tosupport the feasibility of treatment.

WO2009/095418 relates to a method for treating uterine fibroids, whichmethod comprises administering to a patient in need thereof an effectiveamount of ulipristal acetate or any metabolite thereof. The inventorshave shown that a low dosage, e.g. a daily dosage of 5 to 15 mg,preferably 10 mg, ulipristal acetate was the most effective. Ulipristalacetate or any metabolite thereof is particularly efficient to reduce orstop bleeding in a patient afflicted with uterine fibroids, or to reducethe size of uterine fibroids. The patient may be administered with anoral dosage of ulipristal acetate or any metabolite thereof during aperiod of about 2 to about 4 months.

In the prior art there was a strong technical prejudice against thelong-term and repeated administration of SPRM's, for example asoprisnil,mifepristone or ulipristal acetate may induces progesterone-receptormodulator-associated endometial changes, which can be considered asharmful side effects (Mutter G L., Mod. Path. (2008), 1-8; Nieman, L K.,Fertility and Sterility (2011) 95, 2, 767-772.)

Accordingly, UPA have been effective for the treatment of uterinefibroids, but the administration of UPA was limited to a period nolonger than about 2 to about 4 months, preferably 3 months and widelyaccepted by skilled person.

Although treatments for about 2 to about 4 months exist, there remainsignificant unmet needs for improvement of uterine fibroid therapy.

SUMMARY OF THE INVENTION

The present invention provides new treatment method in the field ofuterine fibroid therapy. We have surprisingly found that the technicalprejudice against the long-term and repeated administration of SPRM'swith special regards to UPA was not well-established. Results gainedfrom the clinical study have proven beyond any doubt that theadministration of adequate dosage of ulipristal acetate or of ametabolite thereof for the treatment of uterine fibroids can berepeated. The long-term repeated administration provides a number ofgreat benefits. For example reduction of uterine bleeding (higherpercentage of subjects in amenorrhea), decrease in volume of myomas,reduction in patent-reported pain, etc. were demonstrated. At the sametime the frequency of PAEC (Progesteron receptor modulator-AssociatedEndometrial Changes) was independent of length of treatment.

Accordingly, in one aspect the invention provides a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof in a therapeutically effective amount,wherein said ulipristal acetate or any metabolite thereof is to beadministered in subsequent treatment periods and a treatment periodlasts 2-6 months and each treatment period is followed by a drug-freeperiod.

We have also investigated the possible repeated use of a new method ofcombined treatment where the treatment course of UPA limited to threemonths known from the state of the art was followed by theadministration of a progestin, especially NETA for a period of 5-30 daysand an additional drug-free period. In this way additional benefits ofthis combined treatment have been proven, namely earlier and morepredictable resumption of menstruations and reduction of intensity ofmenstruation especially after the first treatment course of UPA.

So, in the second aspect the invention relates to a method for thetreatment of uterine fibroids comprising administering therapeuticallyeffective amount of ulipristal acetate or any metabolites thereof incombination with a therapeutically effective amount of a progestin,wherein said ulipristal acetate or any metabolite thereof is to beadministered in subsequent treatment period of 2-6 months and progestinis to be administered for a subsequent treatment period of 5-30 days.

It also means that even if the administration of NETA takes placefollowing UPA course limited to the period of about 2 to about 6 monthsthe above-mentioned benefits resulted in the combined treatment areobtained.

Accordingly, in the third aspect the invention also relates to a methodfor the treatment of uterine fibroids comprising administeringtherapeutically effective amount of ulipristal acetate or anymetabolites thereof in combination with a therapeutically effectiveamount of a progestin, wherein said compounds are to be administered ina repetitive manner comprising the followings:

a, administering ulipristal acetate;

b, thereafter administering progestin;

c, thereafter a drug-free period.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to ulipristal acetate or any metabolitesthereof for use in the treatment of uterine fibroids comprisingadministering ulipristal acetate or any metabolites thereof in atherapeutically effective amount, wherein said ulipristal acetate or anymetabolite thereof is to be administered in subsequent treatment periodsand a treatment period lasts 2-6 months and each treatment period isfollowed by a drug-free period.

In a preferred embodiment the invention relates to ulipristal acetate orany metabolites thereof for use in the treatment of uterine fibroidscomprising administering ulipristal acetate or any metabolite thereof,wherein a treatment period lasts 2-4 months.

In a still preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitethereof, wherein a treatment period lasts 12 weeks.

In a more preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitethereof, wherein a drug-free period comprises at least one menstruationcycle.

In a further embodiment the invention relates to ulipristal acetate orany metabolites thereof for use in treatment of uterine fibroidscomprising administering ulipristal acetate or any metabolite thereof,wherein a drug-free period comprises at least two menstruation cycles.

In an other embodiment the invention relates to ulipristal acetate orany metabolites thereof for use in treatment of uterine fibroidscomprising administering ulipristal acetate or any metabolite thereof,wherein a drug-free period comprises at least three menstruation cycles.

In an other preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitethereof, wherein a drug-free period is not more than 6 months.

In a more preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitethereof, wherein said ulipristal acetate or any metabolite thereof is tobe administered daily.

In a still more preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitethereof, wherein ulipristal acetate or any metabolite thereof is to beadministered in a daily amount of 5-15 mg.

In a most preferred embodiment the invention relates to ulipristalacetate or any metabolites thereof for use in treatment of uterinefibroids comprising administering ulipristal acetate, wherein ulipristalacetate is to be administered in a daily amount of 10 mg.

The invention relates to ulipristal acetate or any metabolite thereof incombination with a progestin for use in the treatment of uterinefibroids wherein ulipristal acetate or any metabolite thereof is to beadministered for a treatment period of 2-6 months and progestin is to beadministered for a subsequent treatment period of 5-30 days.

The invention also relates to ulipristal acetate or any metabolitethereof in combination with a progestin for use in the treatment ofuterine fibroids wherein said compounds are to be administered in arepetitive manner comprising the followings:

a. administering ulipristal acetate,

b, thereafter administering progestin,

c, thereafter a drug-free period.

In a preferred embodiment the invention relates to ulipristal acetate orany metabolite thereof in combination with a progestin for use in thetreatment of uterine fibroids wherein progestin is selected from thegroup comprising derivatives of 19-nortestosterone, derivatives of17α-acetoxyprogesterone, levonorgestrel and dospirenone.

In a still preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein progestin isnorethisterone acetate.

In a more preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein norethisterone acetateis to be administered in a daily amount of 5-15 mg.

In a further embodiment the invention relates to ulipristal acetate orany metabolite thereof in combination with a progestin for use in thetreatment of uterine fibroids wherein norethisterone acetate is to beadministered in a daily amount of 10 mg.

In an other embodiment the invention relates to ulipristal acetate orany metabolite thereof in combination with a progestin for use in thetreatment of uterine fibroids wherein ulipristal acetate or anymetabolite thereof is to be administered in a daily amount of 5-15 mg.

In an other preferred embodiment the invention relates to ulipristalacetate in combination with a progestin for use in the treatment ofuterine fibroids wherein ulipristal acetate is to be administered in adaily amount of 10 mg.

In a more preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein ulipristal acetate orany metabolite thereof is to be administered for a treatment period of2-4 months.

In a still more preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein ulipristal acetate orany metabolite thereof is to be administered for a treatment period of12 weeks.

In a most preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein progestin is to beadministered for a treatment period of 10 days.

In a still preferred embodiment the invention relates to ulipristalacetate in combination with a progestin for use in the treatment ofuterine fibroids wherein ulipristal acetate is to be administered for atreatment period of 12 weeks and norethisterone acetate is to beadministered for a treatment period of 10 days.

In a further preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein a drug-free periodcomprises at least one menstruation cycle.

In a preferred embodiment the invention relates to ulipristal acetate orany metabolite thereof in combination with a progestin for use in thetreatment of uterine fibroids wherein a drug-free period comprises atleast two menstruation cycles.

In a most preferred embodiment the invention relates to ulipristalacetate or any metabolite thereof in combination with a progestin foruse in the treatment of uterine fibroids wherein a drug-free periodcomprises at least three menstruation cycles.

The present invention relates to a method for the treatment of uterinefibroids comprising administering ulipristal acetate or any metabolitesthereof in a therapeutically effective amount, wherein said ulipristalacetate or any metabolite thereof is to be administered in subsequenttreatment periods and a treatment period lasts 2-6 months and eachtreatment period is followed by a drug-free period.

In a preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a treatment period lasts 2-4months.

In a still preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a treatment period lasts 12weeks.

In a more preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a drug-free period comprisesat least one menstruation cycle.

In a further embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a drug-free period comprisesat least two menstruation cycles.

In an other embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a drug-free period comprisesat least three menstruation cycles.

In an other preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein a drug-free period is notmore than 6 months.

In a more preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolite thereof, wherein said ulipristal acetate orany metabolite thereof is to be administered daily.

In a still more preferred embodiment the invention relates to a methodfor the treatment of uterine fibroids comprising administeringulipristal acetate or any metabolite thereof, wherein ulipristal acetateor any metabolite thereof is to be administered in a daily amount of5-15 mg.

In a most preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate, wherein ulipristal acetate is to be administered in a dailyamount of 10 mg.

The present invention relates to a method for the treatment of uterinefibroids comprising administering therapeutically effective amount ofulipristal acetate or any metabolites thereof in combination with atherapeutically effective amount of a progestin, wherein said ulipristalacetate or any metabolite thereof is to be administered in subsequenttreatment period of 2-6 months and progestin is to be administered for asubsequent treatment period of 5-30 days.

The present invention also relates to a method for the treatment ofuterine fibroids comprising administering therapeutically effectiveamount of ulipristal acetate or any metabolites thereof in combinationwith a therapeutically effective amount of a progestin, wherein saidcompounds are to be administered in a repetitive manner comprising thefollowings:

a, administering ulipristal acetate;

b, thereafter administering progestin;

c, thereafter a drug-free period.

In a preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein progestin is selected from the group comprising derivatives of19-nortestosterone, derivatives of 17α-acetoxyprogesterone,levonorgestrel and dospirenone.

In a more preferred embodiment the invention relates to a method for thetreatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein progestin is norethisterone acetate.

In a still preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein norethisterone acetate is to be administered in a daily amountof 5-20 mg.

In a still more preferred embodiment the invention relates to a methodfor the treatment of uterine fibroids comprising administeringulipristal acetate or any metabolites thereof in combination with aprogestin, wherein norethisterone acetate is to be administered in adaily amount of 10 mg.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein ulipristal acetate is to be administered in a daily amount of5-15 mg.

In an other preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein ulipristal acetate is to be administered in a daily amount of 10mg.

In a still preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein ulipristal acetate or any metabolites thereof is to beadministered for a treatment period of 2-4 months.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein ulipristal acetate or any metabolites thereof is to beadministered for a treatment period of 12 weeks.

In an other preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein progestin is to be administered for a treatment period of 10days.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein ulipristal acetate or any metabolites thereof is to beadministered for a treatment period of 12 weeks and norethisteroneacetate is to be administered for a treatment period of 10 days.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein a drug-free period comprises at least one menstruation cycle.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein a drug-free period comprises at least two menstruation cycles.

In a further preferred embodiment the invention relates to a method forthe treatment of uterine fibroids comprising administering ulipristalacetate or any metabolites thereof in combination with a progestin,wherein a drug-free period comprises at least three menstruation cycles.

As used herein “administering” refers to contact of a therapeuticallyeffective amount of ulipristal acetate or any metabolites thereof, tothe subject.

Usually, the “subject” is well-recognized in the art, and is used hereinto refer to a mammal and more preferably to a human being, and even morepreferably to a human female.

Uterine fibroids are benign non-cancerous tumors that originate from thesmooth muscle layer, the myometrium and the accompanying connectivetissue of the uterus. Uterine fibroid are also known as myoma, uterinehypertrophy, uterine leiomyomata, leiomyoma, myoma, fibromyoma,leiofibromyoma, fibroleiomyoma, fibroma, myometrial hypertrophy,fibrosis uteri, and fibrotic metritis. Fibroids are the most commonbenign tumors in females with a prevalence of 20-40% in women ofreproductive age (Wallach E E, Vlahos N F. “Uterine myomas: an overviewof development, clinical features, and management”. Obstet Gynecol(2004), 104, 393-406).

As used herein “treatment” or “treating” refers to at least anamelioration (or reduction) and/or preventing the symptoms associatedwith uterine fibroids. Amelioration and/or prevention are used in abroad sense to refer to at least a reduction in the magnitude of aparameter, e.g. symptom. As such, treatment also includes situationswhere the pathological condition, or at least symptoms associatedtherewith, are completely or partially inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the host no longersuffers from the condition, or at least the symptoms that characterizethe condition.

As used herein“therapeutically effective amount” refers to a dosagesufficient to show an effective response as described above.

As used herein “menstrual cycle” refers to the term for thephysiological changes that occur in fertile women and other femaleprimates for the purposes of sexual reproduction. Human menstrual cycle,a “monthly” cycle that can vary around an average of around 28 days percycle.

The chemical formula of uliprital acetate, also known as CDB-2914, is17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione.It is a well-known steroid, more specifically a 19-norprogesterone,which possesses antiprogestational and antiglucocorticoidal activity.This compound, and methods for its preparation, are described in U.S.Pat. Nos. 4,954,490, 5,073,548, and 5,929,262, and international patentapplications WO2004/065405 and WO2004/078709. Properties of thiscompound are further described in Blithe et al, 2003.

An “active metabolite”, as used herein, refers to a product producedthrough metabolism in the body of a specified compound, in the presentcase ulipristal acetate, or salt thereof and which exhibits the samebiological activity as the ulipristal acetate. Such metabolites mayresult for example from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered ulipristal acetate, or of a salt thereof.

Active metabolites of ulipristal acetate, or of a salt thereof, may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchmetabolites may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered ulipristal acetateor of a salt thereof. Accordingly, the invention includes activemetabolites of ulipristal or of a salt thereof, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such metabolite may also be produced in vitro byoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, or enzymatic cleavage of thecorresponding ulipristal acetate or salt thereof. Examples ofmetabolites of ulipristal acetate (CDB-2914), include those described inAttardi et al, 2004, e.g. monodemethylated CDB-2914 (CDB-3877);didemethylated CDB-2914 (CDB-3963); 17α-hydroxy CDB-2914 (CDB-3236);aromatic A-ring derivative of CDB-2914 (CDB-4183).

As used herein, a “progesterone agonist” or “progestin” refers to acompound or agent that activates the progesterone receptor. Theprogestin is selected from the group comprising derivatives of19-nortestosterone, derivatives of 17α-acetoxyprogesterone (pregnanes),levonorgestrel and dospirenone. Preferably, the progestin isnorethindrone (norethisterone) acetate (NETA).

For a brief review of present methods for drug delivery, see, Langer,Science 249:1527-1533 (1990), which is incorporated herein by reference.Methods for preparing administrable compounds are known or are apparentto those skilled in the art and are described in more detail in, forexample, Remington's Pharmaceutical Science, 17th Ed., Mack PublishingCompany. Easton, Pa. (1985), which is incorporated herein by reference.

The mode of administration possibilities include solid compositions suchas tablets, capsules, lozenges, pills, transdermal patches, dentalpastes, suppositories, inhalants, solutions, ointments, parenteraldepots, vaginal rings, vaginal gels and intra-uterine delivery systems.

For solid compositions, conventional nontoxic solid carriers may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharine, talcum, cellulose,glucose, sucrose. For oral administration, a pharmaceutically acceptablenontoxic composition is formed by incorporating any of the normallyemployed excipients, such as those carriers previously listed.

Oral solid dosage forms are preferentially compressed tablets orcapsules. Compressed tablets may contain diluents to increase the bulkof the progesterone receptor modulator, the SPRM, or a metabolitethereof, so that production of a compressed tablet of practical size ispossible. Binders, which are agents which impart cohesive qualities topowdered materials may be also necessary Povidone, starch, gelatin,sugars such as lactose or dextrose, and natural and synthetic gums maybe used. Disintegrants are generally necessary in the tablets tofacilitate break-up of the tablet. Disintegrants include starches,clays, celluloses, algins, gums and crosslinked polymers. Lastly smallamounts of materials known as lubricants and glidants are included inthe tablets to prevent adhesion of the tablet material to surfaces inthe manufacturing process and to improve the flow characteristics of thepowder material during manufacture Colloidal silicon dioxide is mostcommonly used as a glidant and compounds such as talc, magnesiumstearate or stearic acids are most commonly used as lubricants.Procedures for the production and manufacture of compressed tablets arewell known by those skilled in the art (See Remington).

Capsules are solid dosage forms using preferentially either a hard orsoft gelatin shell as a container for the mixture of the progestogenagent or progesterone receptor modulator and inert ingredients.Procedures for production and manufacture of hard gelatin and softelastic capsules are well known in the art (See Remington)

The oral route is preferred. Other routes of administration can besuitable in comparison with oral routes using blood levels to provideclinical success.

Buccal forms or devices are also useful, such as those described in U.S.patent application 20050208129, herein incorporated by reference. U.S.patent application 20050208129 describes a prolonged release bioadhesivemucosal therapeutic system containing at least one active principle,with an active principle dissolution test of more than 70% over 8 hoursand to a method for its preparation. Said bioadhesive therapeutic systemcomprises quantities of natural proteins representing at least 50% byweight of active principle and at least 20/o by weight of said tablet,between 109 and 20 of a hydrophilic polymer, and compression excipients,and comprising between 4% and 10% of an alkali metal alkylsulphate toreinforce the local availability of active principle and between 0.1%and 1% of a monohydrate sugar.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compounds and a sterile vehicle, water being preferred.Ulipristal acetate or a metabolite thereof, depending on the vehicle andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filtered sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanesthetic, preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. The drylyophilized powder is then sealed in the vial and an accompanying vialof water for injection is supplied to reconstitute the liquid prior touse Parenteral suspensions can be prepared in substantially the samemanner except that the compounds are suspended in the vehicle instead ofbeing dissolved and sterilization cannot be accomplished by filtration.The compound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of ulipristal.

Additionally, a suppository can be employed to deliver ulipristal. Theactive compound can be incorporated into any of the known suppositorybases by methods known in the art. Examples of such bases include cocoabutter, polyethylene glycols (carbowaxes), polyethylene sorbitanmonostearate, and mixtures of these with other compatible materials tomodify the melting point or dissolution rate. These suppositories canweigh from about 1 to 2.5 gm.

Transdermal delivery systems comprising a penetration enhancer and anocclusive backing are of use to deliver ulipristal or a metabolitethereof. Examples of penetration enhancers include dimethyl sulfoxide,dimethyl acetamide and dimethylformamide.

Systems comprising polymeric devices which slowly release or slowlyerode and release within the body to provide continuous supplies ofulipristal are also of use. Suitable delivery systems includesubcutaneous devices or implants such as those routinely used to delivernorgestrienone or progestin R2323 and other medicaments.

In some embodiments of the present invention, the pharmaceuticalcompositions suitable for vaginal and/or intrauterine administration arein the form of intravaginal or vaginal rings. These rings are annularlyshaped articles made of inert elastomeric materials that can beintroduced into the vagina in a simple manner without medicalassistance. The ring fits between the rear wall of the vagina and theupper edge of the pubic bone. Numerous types of vaginal rings have beendescribed in the patent and non-patent literature alike. See, e.g., U.S.Pat. Nos. 4,012,496 and 4,155,991 (both to Schopflin et al.); U.S. Pat.No. 4,292,965 (Nash) (which teaches three-layered rings); U.S. Pat. No.3,545,439 (Duncan); U.S. Pat. No. 3,920,805 (Roseman), U.S. Pat. Nos.3,991,760 and 3,995,634 (both to Drobish et al.); U.S. Pat. No.3,995,633 (Gougeon); U.S. Pat. Nos. 4,250,611 and 4,286,587 (both toWong); U.S. Pat. No. 4,596,576 (de Nijs); WO95/00199 (Lehtinen et al.);NL 8500-470-A; and Apter, et al., Contraception 42:285-295 (1990);Burton, et al., Contraception 27:221-230 (1978); Burton et al.,Contraception 19507-516 (1979); Jackanicz, Contraception 24:323-339(1981); Sivin, et al., Contraception 24:341-358 (1981); Timmer, et al.,Contraception 43:629-642 (1990); Toivonen, Contraception 20:511-518(1979); and Sitruk Ware, et al., Contemporary Clin. Gynecol. & Obstet.2:287-98 (2002).

Many basic ring designs are known in the art, e.g., the homogeneousring, two-layered rings, the Roseman ring and three-layered rings. See,e.g., Weiner et al., Acta Obstet Gynecol. Scand, Suppl. 54, 1977 p. 35;U.S. Pat. No. 3,920,805 to Roseman and U.S. Pat. No. 4,012,496 toSchopflen. U.S. Pat. No. 3,545,439 to Duncan and Victor, et al.,Contraception 12:261, 1975. U.S. Pat. No. 4,012,496 to Schoepflin, etal., U.S. Pat. No. 5,972,372. Vaginal rings for use in the presentinvention can be those described in WO2006/010097.

Suitable material providing sustained release of the active ingredientfrom the vaginal ring comprises for example silicone, ethylene vinylacetate (EVA) or polyurethane (PU). Preferred material is EVA or PU.

The pharmaceutical compositions suitable for vaginal and/or intrauterineadministration of the present invention may also take the form of anon-vaginal ring sustained release composition, e.g., gels, foams andsuppositories (e. g, effervescent suppositories) that will provide asustained release of the PRM, SPRM, or active metabolite thereof. Eachof these suitable pharmaceutical compositions will contain at least onepharmaceutically acceptable excipient, carrier or diluent. Personsskilled in the art may select appropriate ones to make the various typesof sustained-release compositions e.g., by resort to standard texts inthe art.

In cases where the progesterone receptor modulator, a SPRM, or ametabolite thereof, is included in a solution, the formulation maycontain suspending agents, as for example, ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, among others.

Useful intranasal formulations of a progesterone receptor modulator, aSPRM, or a metabolite thereof may contain at least one stabilizer and/orone surfactant. Among the pharmaceutically acceptable surfactants arepolyoxyethylene castor oil derivatives, such aspolyoxyethylene-glycerol-triricinoleate, also known as polyoxyl 35caster oil (CREMOPHOR EL), or poloxyl 40 hydrogenated castor oil(CREMOPHOR RH40) both available from BASF Corp.; mono-fatty acid estersof polyoxyethylene (20) sorbitan, such as polyoxyethylene (20) sorbitanmonolaurate (TWEEN 80), polyoxyethylene monostearate (TWEEN 60),polyoxyethylene (20) sorbitan monopalmitate (TWEEN 40), orpolyoxyethylene 20 sorbitan monolaurate (TWEEN 20) (all available fromICI Surfactants of Wilmington, Del.); polyglyceryl esters, such aspolyglyceryl oleate; and polyoxyethylated kernel oil (LABRAFIL,available from Gattefosse Corp.). Preferably, the surfactant will bebetween about 0.01% and 10% by weight of the pharmaceutical composition.Among the pharmaceutically useful stabilizers are antioxidants such assodium sulfite, sodium metabisulfite, sodium thiosulfate, sodiumformaldehyde sulfoxylate, sulfur dioxide, ascorbic acid, isoascorbicacid, thioglycerol, thioglycolic acid, cysteine hydrochloride, acetylcysteine, ascorbyl palmitate, hydroquinone, propyl gallate,nordihydroguaiaretic acid, butylated hydroxytoluene, butylatedhydroxyanisole, alpha-tocopherol and lecithin. Preferably, thestabilizer will be between about 0.01% and 5% by weight of thepharmaceutical composition.

Suspensions may also include chelating agents such as ethylene diaminetetraacetic acid, its derivatives and salts thereof, dihydroxyethylglycine, citric acid and tartaric acid among others. Additionally,proper fluidity of a suspension can be maintained, for example, by theuse of coating materials such as lecithin, by the maintenance of therequired particle size in the case of dispersions and by the use ofsurfactants, such as those previously mentioned. Solid dosage forms fororal administration include capsules, tablets, pills, powders andgranules. In such solid dosage forms, the active compound may be mixedwith at least one inert, pharmaceutically acceptable excipient orcarrier, such as sodium citrate or dicalcium phosphate and/or (a)fillers or extenders such as starches, lactose, sucrose, glucose,mannitol and silicic acid; (b) binders such as carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c)humectants such as glycerol, (d) disintegrating agents such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates and sodium carbonate; (e) solution retarding agentssuch as paraffin; (f) absorption accelerators such as quaternaryammonium compounds; (g) wetting agents such as cetyl alcohol andglycerol monostearate; (h) absorbents such as kaolin and bentonite clay;and (i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

Preferably, ulipristal acetate, is orally administered in atherapeutically daily effective amount of 5 to 15 mg, preferably 5 to 12mg, more preferably 8 to 10 mg, even more preferably 10 mg.

When ulipristal acetate or a metabolite thereof is administered incombination with a progestin, in particular with NETA, thetherapeutically daily effective amount of the progestin is 5 to 20 mg,preferably 5 to 15 mg, more preferably 8 to 10 mg, even more preferably10 mg.

The administration period is from 5 days up to 30 days, preferably from8 days up to 15 days, more preferably 10 days.

As used herein, the term “long-term” administration means in relation tothe expression therapy for treatment of uterin fibroids refers to aperiod of approximately 6 months or longer.

The present invention also contemplates a kit for a long-term treatmentcomprising the SPRM or any metabolite thereof, optionally withprogestins and/or instructions for use.

Generally, the Kit comprises a container and a label or package inserton or associated with the container. Suitable containers include, forexample, bottles, vials, syringes, etc. The containers may be formedfrom a variety of materials such as glass or plastic. The containerholds the progesterone receptor modulator, or any metabolite thereof ofthe invention which is effective for normalizing menstrual bleeding onthe long-term in a subject suffering from a benign gynecologicaldisease. The label or package insert indicates that the composition isused for treating the condition of the invention.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications without departing fromthe spirit or essential characteristics thereof. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of said steps or features.The present disclosure is therefore to be considered as in all aspectsillustrated and not restrictive, the scope of the invention beingindicated by the appended Claims, and all changes which come within themeaning and range of equivalency are intended to be embraced therein.

Various references are cited throughout this specification, each ofwhich is incorporated herein by reference in its entirety.

The foregoing description will be more fully understood with referenceto the following Examples. Such Examples, are, however, exemplary ofmethods of practicing the present invention and are not intended tolimit the scope of the invention.

LIST OF FIGURES

FIG. 1: Median return to menstruation following end of UPA treatment andPBAC assessment on intensity of menstrual bleeding of first menstruationafter end of treatment

FIG. 2: Percentage of subjects in amenorrhea at the end of eachtreatment courses

FIG. 3: Percentage of subjects with spotting or no bleeding at the endof each treatment courses

FIG. 4: Median percent change showing efficacy of fibroid volumereduction after UPA treatment

FIG. 5. Median return to menstruation following end of UPA treatment

FIG. 6. Median PBAC assessment on intensity of menstrual bleeding offirst menstruation after end of treatment

FIG. 7: Endometrial histology (bening endometrium, hyperplasia, polyps)after UPA treatment

FIG. 8: Endometrial histology (PAEC) after UPA treatment

EXAMPLES Example 1

Multicenter, Phase III Study to Investigate the Efficacy and Safety of3-Months of Treatment with UPA Followed by 10 Days of Treatment withNETA or Placebo

All patients received a 3-month treatment course of UPA 10 mg once-dailyfollowed by randomized oral NETA 10 mg once-daily or matching placebofor 10 days. UPA treatment was started during the first 4 days ofmenstruation. NETA or placebo was taken daily for the first 10 daysfollowing the cessation of UPA. The schedule incorporated the potentialfor women to enter an extension study involving repeated intermittentcourses of UPA 10 mg.

Parameters Assessed

In the clinical trial the effect of treatment of uterine fibroids havebeen assessed by means of parameters such as uterine bleeding using thepictorial blood-loss assessment chart (PBAC), condition of the uterususing transvaginal ultrasound (TVUS) and endometrial biopsy, endometrialhistology using endometrial biopsy and pain using the Short-Form McGillPain Questionnaire (SF-MPQ and quality of life using the Uterine FibroidSymptom and Health-Related Quality of Life (UFS-QoL) questionnaire.

The efficacy end points were: percentage of amenorrheic patients at theend of UPA treatment; change from baseline in the volume of the threelargest myomas to end of UPA treatment and 2 weeks after menstruationfollowing end of NETA/placebo treatment, and change from baseline inpain and QoL to end of UPA treatment.

The safety endpoints included the number and proportion of patientsexperiencing treatment-emergent adverse events (TEAEs), includingclinically significant changes in vital signs, physical examination,gynecological or breast examination, electrocardiogram (ECG), ovarianultrasound, changes from baseline in endometrial thickness andclinically significant changes in endometrium biopsy. Other safetyendpoints were change from baseline in hematology, coagulation,biochemistry, lipids, adrenocorticotropic hormone (ACTH), thyroidstimulating hormone (TSH) and prolactin, as well as serum levels ofestradiol (E2).

Exploratory endpoints included assessment of the strength of the firstmenstruation after UPA treatment (using PBAC), time to return ofmenstruation following treatment end, and frequency of post-treatmentPAEC observed in the endometrial biopsy after return of menstruation.

Results Efficacy Endpoints Amenorrhea

At the end of UPA treatment, 164 women (78.5%) were amenorrheic (95% CI,72.4 to 83.5%). The mean and median time from first day of menstruationon, or just prior to, first dose of UPA to amenorrhea were 10.6 and 5.0days respectively, with a range of 2 to 60 days. From day 10 until endof treatment <5% of patients on any particular day reported anybleeding, and <2% reported heavy bleeding.

Fibroid Volume

The median change in the combined volume of the largest three fibroidsbetween baseline and end of UPA treatment was −45.1% (interquartilerange [IQR], −66.1 to −24.9%). This decrease was maintained after UPAtreatment and return of menstruation (median change, −45.8%; IQR, −63.3to −13.0%). In 74.7% of the women there was a ≥25% reduction in thevolume of the three largest fibroids.

Pain Relief and Quality of Life

An improvement in pain was recorded with median change from baselinescores at Weeks 5, 9 and end of UPA treatment of −5.0 (IQR, −12.0 to−1.0), −6.0 (IQR, −14.0 to −1.6) and −6.0 (IQR, −14.0 to −2.0)respectively. Similarly, pain assessed by the VAS showed a decrease(improvement) in score, from a median baseline level of 38 (IQR, 17 to63). Median change was −21 (IQR, −39 to −2), −26 (IQR, −54 to −7) and−25 (IQR, −54 to −6) at Weeks 5, 9 and at end of UPA treatmentrespectively. Patients had moderately severe symptoms and moderatelyimpaired QoL at baseline. After UPA treatment, women showed animprovement in QoL, defined by a median change from baseline score of−34.4 (IQR, −46.9 to −21.9) for symptom severity and a median increaseof 28.5 (IQR, 11.6 to 44.0) for the health-related QoL (HRQL) totalscore compared to baseline.

Safety Endpoints

Three serious adverse events (SAEs) were reported for two patientsduring the study. All occurred post-treatment and were considered notrelated to study medication. One subject was hospitalized due to twoepisodes of excessive uterine bleeding 28 days after completion ofdouble-blind treatment. The other subject had right lobular breastcancer and was withdrawn from the study.

During UPA treatment, 318 TEAEs occurred in 120 women (57.4%), with 3.8%classified as severe. One hundred and twelve TEAEs in 62 women (29.7%)were considered to be UPA related. No SAE occurred during the UPAtreatment phase. Only one TEAE (continuous headache of moderateintensity) led to treatment withdrawal. TEAEs occurring in >3%/o ofwomen were headache (16.3%), nasopharyngitis (6.7%), hot flushes(4.8%0/), fatigue (4.3%), breast discomfort/tenderness (3.8%), pelvicpain (3.8%), vertigo (3.8%), nausea (3.8%) and lower abdominal pain(3.3%).

In the double-blind treatment phase 18 events were reported by 11 women(11.2%) in the NETA group and two events by two women (1.9%) in theplacebo group. In the post-treatment phase, TEAEs were reported in 26.5%and 27.2% of women in the NETA and placebo groups respectively.

During UPA treatment, E2 levels were generally at mid-follicular phaselevels. The mean E2 level was 149.9pg/mL (median, 120.0pg/mL) atscreening and at Visit 5 the mean E2 level was 81.6pg/mL (median,55.0pg/mL). No significant changes in ACTH, TSH, or prolactin wererecorded. A small number of patients had a marginal increase in hepatictransaminases which all resolved during continued treatment and/or bythe time of the follow-up visit.

Exploratory Endpoints Menstrual Bleeding

Median return to menstruation following end of UPA treatment was 14.0days (range, 2 to 42 days) for the NETA treatment group compared to 25days in those receiving placebo (range, 1 to 62 days) (p≤0.001) (FIG. 1)

The overall total median change in PBAC score of the first menstruationfollowing treatment completion compared to that at baseline was −91.5(IQR, −220 to 23), with a median baseline score of 216. The medianchange in PBAC score for the NETA treatment group was −122 (IQR, −229 to−9) compared to −69 (IQR, −167 to 40) for the placebo group (p=0.012).(FIG. 1)

Endometrial Histology Following Double-Blind Treatment

Endometrial histology was benign in all cases. The percentage ofnon-physiological endometrial features was higher after UPA treatmentthan at screening (10.9% at screening vs. 25.6% after UPA treatment)with no significant difference between NETA and placebo groups (28.3% inthe placebo group and 22.6% in the NETA group). However, after NETAtreatment extensive cyst formation (one of the features of PAEC) wasless frequent compared to placebo (2.4% in the NETA group vs. 12.0% inthe placebo group).

The biopsy 12 weeks after UPA treatment confirmed benign endometrialhistology in all biopsies (n=38); one benign endometrial polyp wasreported in the NETA group. At this time in this subgroup, there was nocase of PAEC in the NETA group and only one case in the placebo groupwhich comprised epithelial changes and extensive cystic formation.

Endometrial Thickness

There was a small increase in the percentage of women with endometrialthickness >16 mm by the end of UPA treatment (9.1% vs. 1.5% atscreening). Results for the double-blind treatment groups show smallincreases after NETA (3.5% vs. 0% at screening) and placebo (9.5% vs.3.0% at screening). Endometrial thickness was comparably influenced byNETA and placebo. Three months later, none of the patients assessed hada thickness >16 mm.

Example 2

Long-Term Extension of a Multicenter, Phase III Study to Investigate theEfficacy and Safety of 3-Months of Treatment with UPA Followed by 10Days of Treatment with NETA or Placebo in Subjects with Myomas and HeavyUterine Bleeding

The study consisted of three periods of 3 months open-label UPAtreatment, each followed by 10 days of double-blind treatment with NETAor placebo and then a drug-free period. Subjects were randomly assignedto a NETA or matching placebo arm with a 1:1 ratio.

In study described in Example 1, 251 subjects were screened at 21 sitesand 209 subjects started treatment with UPA of which 202 attended theend of UPA treatment visit. Of those that completed study of Example 1(190 subjects), 132 subjects from 19 sites opted to continue in to theextension study.

In the study of Example 1 and for each present study courses, UPA 10 mgwas orally administered once daily for a period of 90 days, followed by10 mg NETA or matching placebo once daily for a period of 10 days. Thefirst treatment course in the present study consisted of 90 days UPA 10mg treatment followed by 10 days of double-blind treatment (same as inExample 1 study) started between the first and fourth day ofmenstruation (inclusive) following visit after the end of treatment, orone month later if uterine sparing surgery had been performed and myomaswere still present. The second and third treatment courses of thepresent study started on the first day of menstruation following visitsafter ends of each treatment courses, respectively.

Parameters Assessed

Parameters assessed are the same as it was described in Example 1.

Results Efficacy Endpoints Amenorrhea

The study demonstrated that intermittent courses of UPA 10 mg daily oraltreatment for 3 months were effective in the reduction of uterinebleeding, although there was evidence that the effectiveness of 1 sttreatment course was lower than for 2nd-4th courses. Of the 132 subjectsin the ITT Population, the percentage of subjects in amenorrhea at theend of 1, 2, 3 and 4 treatment courses were 79.5%, 88.5%, 88.2% and89.7%, respectively (see FIG. 2), and the mean (median) time toamenorrhea (time from the first dose of UPA in each treatment course tothe start of amenorrhea) was 9.4 days (4.0 days), 3.3 days (2.0 days),5.3 days (3.0 days) and 4.2 days (3.0 days), respectively. Over days9-90, more than 9 days of any level of bleeding (heavy bleeding,bleeding or spotting) were reported by 21 (15.9%), 8 (6.3%), 4 (3.4%)and 4 (3.9%) subjects (ITT Population) (see FIG. 3). The results for theindividual placebo and NETA treatment groups were relatively similar.

Fibroid Volume

The total volume of the 3 largest myomas identified at screening wasshown to decrease following each treatment course, with a maximumdecrease seen at the end of 4th treatment course when a mean (median)percent change from screening of −53.53% (−72.08%) was observed. Thisdecrease was maintained, although reduced, up to the follow-up visit(approximately 2 weeks after the third menstruation following 4thtreatment course), when a mean (median) percent change from screening of−33.68% (−58.84%) was reported (FIG. 4). The uterine volume measured byUS also decreased during the study and similarly maintained after end oftreatment, even so due to the focused mechanism of action of ulipristalacetate, the reduction was less than seen for the volume reduction ofthe 3 largest myomas.

Pain Relief and Quality of Life

The reduction in uterine bleeding and volume of the myomas wasaccompanied by a reduction in patient-reported pain, as measured by theShort-Form McGill Pain Questionnaire (SF-MPQ), the 3 SF-MPQ Partsdemonstrated improvement from baseline at all visits. The results weresimilar for the placebo and NETA treatment groups, as for the overalltreatment group. Quality of life was measured using the specific UterineFibroid Symptom and Health-Related Quality of Life (UFS-QoL) symptomseverity and health-related QoL (HRQL) scales, and also by the generalEuroQoL-5 Dimensions (EQ-5D) questionnaire. In the UFS-QoL the averagesymptom severity score showed an improvement (decrease) from baseline,there was also an improvement (increase) on average for the HRQL totalscore compared to baseline. In the ED-5D questionnaire the most commonproblems reported at baseline and throughout the study were in thepain/discomfort and anxiety/depression dimensions, and for both of thesemeasures improvement was sustained throughout the study.

Following the end of each treatment course al but 4 subjects withavailable data returned to menstruation. As anticipated, median times toreturn of menstruation following discontinuation of UPA 1-4 treatmentcourses were significantly shorter for subjects from the NETA groupcompared to those from the placebo group (p<0.001) (FIG. 5). Inaddition, the heaviness of bleeding as measured by the PBAC score (days1-8), was greater in subjects from the placebo group after eachtreatment course. Bleeding for both groups appeared to decrease aftereach subsequent treatment course, although this was most noticeable insubjects from the NETA group (FIG. 6).

One demonstration of the efficacy, safety and acceptability of UPAtreatment in this patient population is the change in surgery undertakenat the end of the study compared to that initially planned. At the startof study of Example 1, surgery was planned for 66 (50%) of the 132subjects in the ITT population, but by the end of present study surgerywas not performed for 125 (94.7%) subjects; only 7 subjects underwentsurgery.

Safety Endpoints

Safety assessments including vital signs, laboratory and endocrinemeasurements, as well as reported treatment-emergent adverse events(TEAEs) and Serious Adverse Event (SAEs) demonstrated that thisintermittent repeated administration schedule is well tolerated and didnot lead to the identification of any new safety concerns. As might beexpected, the number of TEAEs reported during the first UPA treatmentcourse, was greater than seen in subsequent treatment courses, noincrease in frequency for any TEAE could be observed. Overall, few TEAEswere reported during double-blind treatment; the addition of NETA 10 mgfor 10 day after each treatment course of UPA did not raise any safetyconcerns.

As reported in previous studies, following treatment with a singletreatment course of 3 months UPA, an increase in endometrium thicknesswas observed. However, the increase in endometrium thickness weremonitored after each treatment courses and endometrium thickness datafor the 2 treatment groups were compared. Thickness data for subjectsfrom the placebo group were higher compared to those for the NETA group,and more subjects from the placebo group had endometrium thickness >16mm at each of these visits.

Endometrium biopsy samples were evaluated by 3 independent pathologists.All biopsy samples had a diagnosis of benign endometrium by consensusreview (FIG. 7). Observations of non-physiological changes inendometrium biopsy samples suggested that the incidence was highest insamples taken following first treatment course and second treatmentcourse, including epithelial changes, unusual vascular changes andextensive cyst formation (FIG. 8). At the follow-up visit, thenon-physiological changes were similar to observations seen atscreening, suggesting rapid reversal of changes once treatment hadended.

1-10. (canceled)
 11. A method of treating uterine fibroids in a patientin need thereof, comprising administering to the patient ulipristalacetate or a metabolite thereof in a therapeutically effective amount insequential treatment periods, wherein each treatment period lasts 2-6months and each treatment period is followed by a drug-free period. 12.The method of claim 11 wherein each treatment period lasts 2-4 months.13. The method of claim 11, wherein each treatment period lasts 12weeks.
 14. The method of claim 11, wherein the drug-free periodcomprises at least one menstruation cycle.
 15. The method of claim 11,wherein the drug-free period comprises at least two menstruation cycles.16. The method of claim 11, wherein the drug-free period comprises atleast three menstruation cycles.
 17. The method of claim 11, wherein thedrug-free period is not more than 6 months.
 18. The method of claim 11,wherein the ulipristal acetate or a metabolite thereof is administereddaily.
 19. The method of claim 18, wherein the daily amount is 5-15 mgulipristal acetate or a metabolite thereof.
 20. The method of claim 19,wherein the daily amount is 10 mg ulipristal acetate. 21-50. (canceled)